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Blood, 30 July 2009, Vol. 114, No. 5, pp. 1053-1062. Prepublished online as a Blood First Edition Paper on April 30, 2009; DOI 10.1182/blood-2008-10-186536. This Article Full Text Full Text (PDF) Supplemental Tables and Figure All Versions of this Article: blood-2008-10-186536v1 114/5/1053    most recent Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Rights and Permissions Citing Articles Citing Articles via CrossRef Google Scholar Articles by Remke, M. Articles by Kulozik, A. E. PubMed PubMed Citation Articles by Remke, M. Articles by Kulozik, A. E. Related Collections Lymphoid Neoplasia Clinical Trials and Observations Social Bookmarking                   What's this?  Previous Article  |  Table of Contents  |  Next Article  LYMPHOID NEOPLASIA High-resolution genomic profiling of childhood T-ALL reveals frequent copy-number alterations affecting the TGF-β and PI3K-AKT pathways and deletions at 6q15-16.1 as a genomic marker for unfavorable early treatment response Marc Remke1,*, Stefan Pfister1,2,*, Corinne Kox2, Grischa Toedt1, Natalia Becker1, Axel Benner3, Wiebke Werft3, Stephen Breit2, Shuangyou Liu2, Felix Engel1, Andrea Wittmann1, Martin Zimmermann4, Martin Stanulla5, Martin Schrappe5, Wolf-Dieter Ludwig6, Claus R. Bartram7, Bernhard Radlwimmer1, Martina U. Muckenthaler2, Peter Lichter1,, and Andreas E. Kulozik2, 1 German Cancer Research Center (DKFZ), Division Molecular Genetics, Heidelberg; 2 Department of Pediatric Oncology, Hematology and Immunology, University of Heidelberg, Heidelberg; 3 DKFZ, Division Biostatistics, Heidelberg; 4 Department of Pediatric Hematology and Oncology, Hannover Medical School, Hannover; 5 Department of Pediatrics, University Medical Center Schleswig-Holstein, Campus Kiel, Kiel; 6 HELIOS Klinikum Berlin, Charité-University Medical School Berlin, Robert-Rössle-Clinic, Campus-Buch, Berlin; and 7 Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany Precursor T-cell acute lymphoblastic leukemia (T-ALL) in children represents a clinical challenge, because relapses are usually fatal. It is thus necessary to identify high-risk patients as early as possible to effectively individualize treatment. We aimed to define novel molecular risk markers in T-ALL and performed array-based comparative genomic hybridization (array-CGH) and expression analyses in 73 patients. We show that DNA copy-number changes are common in T-ALL and affect 70 of 73 (96%) patients. Notably, genomic imbalances predicted to down-regulate the TGF-β or up-regulate the PI3K-AKT pathways are identified in 25 of 73 (34%) and 21 of 73 (29%) patients, suggesting that these pathways play key roles in T-ALL leukemogenesis. Furthermore, we identified a deletion at 6q15-16.1 in 9 of 73 (12%) of the patients, which predicts poor early treatment response. This deletion includes the CASP8AP2 gene, whose expression is shown to be down-regulated. The interaction of CASP8AP2 with CASP8 plays a crucial role in apoptotic regulation, suggesting a functional link between the clinical effect of the deletion and the molecular mode of action. The data presented here implicate the TGF-β and PI3K-AKT pathways in T-ALL leukemogenesis and identify a subgroup of patients with CASP8AP2 deletions and poor early treatment response. CiteULike    Connotea    Del.icio.us    Digg    Reddit    Technorati    What's this?

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